**Abstract**

The new coronavirus first appeared in December 2019 in Wuhan, China, being officially named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the International Committee on Taxonomy of Viruses (ICTV), as well as the name of the disease has been described as COVID-19 (coronavirus disease 2019). In March 2020, the disease was considered a global pandemic, with currently more than 514 million cases worldwide, with 6.4 million deaths. Severe cases of COVID-19 progress to acute respiratory distress syndrome (ARDS), on average about 8–9 days after the onset of symptoms. It is also worth mentioning that the severity of the disease in patients is not only due to the viral infection but also due to the host response. This phase, called a cytokine storm, reflects a state of systemic immune activation, with high levels of cytokines, such as IL-6, IL-1b, IL-2, IL-12, IL-18, TNF, and interferon gamma (IFN-γ). In this sense, the management of the disease largely depends on symptomatic and supportive treatments. For severely or critically ill patients with acute respiratory distress syndrome (ARDS) and sepsis, in addition to supplemental oxygen, mechanical ventilation, and ARDS-specific therapies, antiviral and antibiotic treatments should also be considered. Thus, the purpose of this chapter is to describe the pathophysiology and treatment of SARS-CoV-2 infection.

**Keywords:** SARS-CoV-2, COVID-19, pathophysiology, treatment

### **1. Introduction**

Coronaviruses (CoVs) belong to the *order of Nidovirales*, *family of Coronaviridae*, *and* are divided into four genera: *alphacoronavirus, betacoronavirus, gammacoronavirus, and deltacoronavirus*. The term "Corona" is used because the virus has crown-like spikes on its external surface [1]. CoVs cause diseases in a wide variety of birds and mammals and have been found in humans since 1960. To date, seven human CoVs have been identified, including the alpha-CoVs HCoVs-NL63 and HCoVs-229E and the beta-CoVs HCoVs-OC43, HCoVs-HKU1, severe acute respiratory syndrome-CoV (SARS-CoV), and Middle East respiratory syndrome-CoV (MERS-CoV). The new coronavirus was first identified in December 2019 in Wuhan, China, being officially

named by the International Committee on Virus Taxonomy (ICTV), as well as the name of the disease has been designated COVID-19 [2, 3].

SARS-CoV-2 is very contagious since it is able to spread easily from human to human through different routes of infection, such as droplets, contact, and aerosol transmission. Coronaviruses (CoVs) are the largest known RNA viruses, their size ranges from 65 to 125 nm in diameter, and their nucleic acid genome is a single-tape RNA, with a size ranging from 26 to 32 Kb. The CoVs HKU1, NL63, OC43, and 229E are associated with mild symptoms in humans, while SARS-CoV, MERS-CoV, and SARS-CoV-2, which belong to the genus betacoronavirus, cause severe pneumonia in humans [3].

CoVs were believed to infect only animals until an outbreak of severe acute respiratory syndrome (SARS) caused by SARS-CoV occurred in 2002 in Guangdong, China. A decade later, another pathogenic coronavirus, known as middle eastern respiratory syndrome coronavirus (MERS-CoV), caused an endemic disease in Middle Eastern countries. In late 2019, Wuhan, an emerging business center in China, experienced an outbreak of a new coronavirus that killed more than 1,800 people and infected more than 70,000 in the first fifty days of the epidemic. From the sequencebased analysis of isolates from patients, the virus was identified as a new coronavirus. In a recent review, it was demonstrated that the epicenter of the COVID-19 pandemic was similar to that of SARS-CoV-1, that is, a zoonotic origin. The most robust evidence points out that the Huanan market was the epicenter of the pandemic, probably the wildlife trade [4].

Because it is an RNA virus, SARS-CoV-2 presents a high mutation rate as its characteristic. This aspect provides conditions for this viral zoonotic pathogen to become more efficiently transmitted from person to person and possibly becoming more virulent. These observations indicated the ability of this virus to contaminate from human to human, which was subsequently reported worldwide [5]. In this sense, in March 2020, the disease was considered a global pandemic. Since then, there have been more than 575 million cases and 6.4 million deaths worldwide, according to data of the World Health Organization (WHO) in July 2022. In the same period, in Brazil, there were 33 million cases, with 679,000 deaths. The mortality rate in this country, according to the Brazilian Ministry of Health, is 32 people per 100,000 habitants.

Considering the epidemiological aspects of the pandemic, with emphasis on the mortality of COVID-19, disease therapy is a decisive tool in the conduction of patients and is fundamental for clinical improvement. Without specific treatment established for COVID-19 up to now, therapeutic support, such as the use of corticosteroids and oxygen supplementation, delivered the best results in large *trials.* In addition, interleukin blockers presented a good response in patients with the potential to progress to cytokine storm and acute respiratory distress syndrome (ARDS). Thus, the objective of this chapter is to describe the pathophysiology and treatment of SARS-CoV-2 infection, highlighting the importance of inflammatory biomarkers and knowledge of pathophysiology, and their interaction for early recognition of therapeutic targets (corticosteroids, oxygen supplementation), the need for hospitalization in intensive care units, as well as predict the evolution of the disease.

### **2. COVID-19**

COVID-19 is a disease with high contagious power and clinical manifestations ranging from mild to severe, with the majority of the cases being mild. In current

#### *COVID-19: From Pathophysiology to Treatment DOI: http://dx.doi.org/10.5772/intechopen.107146*

data, 81% of cases present mild symptoms and 1.2% are asymptomatic. The WHO estimates the reproductive number (R0) of SARS-CoV-2 between 2 and 2.5, which is higher than SARS (1.7–1.9) and MERS (<1), and demonstrates the highest pandemic potential of SARS-CoV-2. SARS-CoV-2 can spread rapidly in the community, unlike SARS-CoV and MERS-CoV, which have a higher mortality rate and a higher hospital admission rate [3]. Two main strains called "A" and "B" helped to track and know the viral genome of SARS-CoV-2, the difference between these two strains is only two nucleotides, and these characteristics are also found in coronavirus *of Rhinolophus*, the supposed host reservoir. Strain B has been the most common in the entire pandemic and includes all eleven sequenced human genomes directly associated with the Huanan market, The oldest human-line A genomes do not have a direct epidemiological connection with the Huanan market but have been identified in patients who have circulated in the vicinity of the market [6].

To enter host cells, SARS-CoV-2 shares the same human cell receptor with SARS-CoV, the angiotensin 2 converting enzyme (ACE-2), which is an ectoenzyme anchored in the plasma membrane of cells of various tissues, mainly in the lower respiratory tract, heart, kidneys, and gastrointestinal tract. The first critical step for the entry of the virus into sensitive host cells involves a specific receptor, usually, the CoVs enter the host cell using the transmembrane Spike glycoprotein (S). After the viral anchorage, transmembrane serine protease 2 (TMPRSS2) cleaves and activates the Spike protein: S1 binds to the receptor through its receptor-binding domain and S2 fuses the host membrane with the viral counterpart, an event that allows SARS-CoV-2 to enter the cells by endocytosis or direct fusion of the viral envelope with the host membrane [7].

Active replication and virus release cause the host cell to suffer pyroptosis and the discharge of pro-inflammatory chemical mediators, which are recognized by neighboring epithelial cells, endothelial cells, and alveolar macrophages, triggering the generation of pro-inflammatory and chemokine cytokines, including IL-6. Chemokines and pro-inflammatory cytokines attract monocytes, macrophages, and T cells to the site of infection, increasing the inflammatory picture (with the addition of IFNγ produced by T cells) and establishing a pro-inflammatory feedback cycle (**Figures 1** and **2**) [8].

In an impaired immune response, there may be a greater accumulation of immune cells in the lungs, causing overproduction of pro-inflammatory cytokines, which damages the lung infrastructure. The resulting cytokine storm circulates to other organs, promoting damage to various organs. In addition, non-neutralizing antibodies produced by B cells can increase SARS-CoV-2 infection through antibody-dependent enhancement, further exacerbating organ damage. Alternatively, in a healthy immune response, initial inflammation attracts virus-specific T cells to the site of infection, where they can eliminate infected cells before viral spread. Neutralizing antibodies in these individuals can block viral infection, and alveolar macrophages recognize neutralized viruses and apoptotic cells and eliminate them by phagocytosis, generating minimal inflammatory damage [8].

The mean incubation period of COVID-19 is 5 to 6 days, the mean age of COVID-19 cases ranges from 49 to 57 years, and the mean time from the first symptom to death is 14 days. Within 5 to 6 days of the onset of symptoms, the viral load of SARS-CoV-2 reaches its peak, being significantly earlier than that of SARS-CoV, in which the period of viral load peak is about 10 days after the onset of symptoms [9].

#### **Figure 1.**

*Connection of SARS-CoV-2 to ACE-2 receptors. Figure describes: The connection of SARS-Cov-2 with the ACE2 receptor on the target cell, followed by cleavage of SARS-CoV-2 with the S protein, activation of the S2 domain, and fusion of the viral membrane with the host cell. Source: Figure of the authors.*

#### **Figure 2.**

*Viral replication of SARS-CoV-2. Figure describes: 1) Fusion of the virus to the host membrane, occurring endocytosis; 2) Exposure of the viral genome; 3) viral polymerase performs transcription for viral protein; 4) viral replication occurs; 5) genomic replication; 6) transition of the virus into proteins in the membrane of the endoplasmic reticulum; 7) proteins S, E, and M recombining with nucleocapsid; 8) viruses within the Golgi capsule, performing viral maturation; and 9) viral exocytosis. Source: Figure of the authors.*

Severe cases of COVID-19 progress to acute respiratory distress syndrome (ARDS), on average, about 8–9 days after the onset of symptoms. It is also worth mentioning that the severity of the disease in patients is not only due to viral infection but also due to the response of the host [8], as shown in **Figures 3** and **4**.

*COVID-19: From Pathophysiology to Treatment DOI: http://dx.doi.org/10.5772/intechopen.107146*

#### **Figure 3.**

*Innate and adaptive immune response at COVID-19. Description of the most frequent cellular alterations in COVID-19: increase of neutrophils and decrease of eosinophils, monocytes, and basophils. Lymphopenia occurs due to a decrease in CD4, Cd8, B and natural killer lymphocytes. The activated T lymphocyte promotes the increase of TNF, Interferon, and IL-2. The activation of B lymphocytes promotes the increase of immunoglobulins G. In the storm of cytokines occurs an uncontrolled elevation of IL-6, IL-1, TNF, interferon gamma, and IL-10. Source: Figure of the authors.*

SARS-CoV-2 infection in severe cases leads to activation of macrophages and dendritic cells and consequent exacerbated release of pro-inflammatory cytokines. In addition, the presentation of SARS-CoV-2 antigens through the main histocompatibility complexes I and II (MHC I and II) stimulates humoral and cellular immunity, also resulting in the high production of cytokines. When the virus reaches the lower respiratory tract and infects type II pneumocytes, it promotes apoptosis and loss of surfactant, capillary extravasation, and alveolar edema, resulting in lung damage and collapse, impairing gas exchange [10].

The onset and duration of the cytokine storm vary, depending on the cause and treatments administered. Most patients with cytokine storm present fever, fatigue, anorexia, headache, rash, diarrhea, arthralgia, myalgia, and neuropsychiatric findings. These symptoms may be directly due to cytokine-induced tissue damage or acute phase physiological changes or may result from immune cell-mediated responses. Cases may progress rapidly to disseminated intravascular coagulation with vascular

#### **Figure 4.**

*Cytokine storm at COVID-19. Description of the pathophysiology of cytokine storm, after the entry of the virus into the pneumocyte, occurs activation of macrophages with the release of cytokines, generating damage to lung cells, with fibrin formation, increased vascular permeability, and pulmonary edema. Source: Figure of the authors.*

occlusion or catastrophic hemorrhage, dyspnea, hypoxemia, hypotension, hemostatic imbalance, septic shock, and death [11].

Since the initial phase of the pandemic, the cytokine storm has become peculiar to SARS-COV-2 infection, at least in severe cases. It is responsible for damaging the respiratory tract and subsequent failure of multiple organs. It results from a complex network involving cytokines/chemokines/infiltrating immune cells that orchestrate the aberrant immune response in COVID-19. This term covers several disorders of immune dysregulation and is characterized by constitutional symptoms, systemic inflammation, and multiple organ dysfunction [12].

The combination of hyperinflammation, coagulopathy, and low platelet count puts patients with cytokine storm at high risk of spontaneous bleeding. Among the most commonly described biomarkers are interleukin I 1β, IL-6, tumor necrosis factor (TNF) α, interferon (IFN) γ, and IL-10. The cytokine storm sustains too much inflammatory response in the blood, causing the immune system to attack the body involving various organs, such as the lungs. This, in turn, causes injury to the alveolar-capillary membrane, increased pulmonary permeability, acute respiratory distress syndrome, and multiple organ failure [13].

In the pathophysiology of cytokine storm, we can highlight macrophage activation, a hyperinflammatory condition associated with different triggers, including infections, autoimmune diseases, and neoplasms, being characterized by fever, hepatosplenomegaly, cytopenias, elevated levels of ferritin, triglycerides, lactic dehydrogenase, D-dimer and aminotransferases, as well as hypofibrinogenemia. The acute phase of the syndrome reflects a state of systemic immune activation, with elevated cytokine levels such as IL-6, IL-1b, IL-2, IL-12, IL-18, TNF, and interferon gamma (IFN-γ). The term macrophage activation syndrome (AMS) refers to a subgroup of patients with secondary hemophagocytic lymphohistiocytosis, in a context of self-ignition or systemic autoimmunity, characterized by hyperinflammatory and hyperferritinemic immune responses, directed by different T lymphocyte subpopulations and associated with cytokine release syndrome [9], as illustrated in **Figure 4**.
